The Neonatal abstinence Syndrome (NAS) is a complex of signs and symptoms in the postnatal period associated with the sudden withdrawal of maternally transferred opioids. Optimal treatment for NAS has not been established, with only modest changes in treatment approaches over the past ~25 years. Despite the difficulties in conducting research in a vulnerable neonatal population, it is self-evident that successful advances in adult addiction be tested, validated, and transferred to infants with NAS. Administration of oral morphine is associated with lengths of treatment of 8-79 days in the hospital setting. We have performed the only clinical trial employing sublingual buprenorphine to treat NAS and have demonstrated a reduction in length of treatment from 33 to 22 days relative to standard of care morphine treatment. Our initial investigation, however, was a phase one, unblinded design. To meet level 1a evidence standards, a randomized controlled trial employing a subjective measurement driving the primary and secondary endpoints must have double blinding. The purpose of the current investigation is to test the central hypothesis that sublingual buprenorphine is more efficacious than oral morphine solution in the treatment of NAS. We specifically aim to demonstrate that sublingual buprenorphine has an efficacy advantage over morphine for the clinical endpoints of length of treatment and duration of hospitalization. From our initial investigations we have built a pharmacokinetic/pharmacodynamic (PK/PD) model. We will build upon this model, identify covariates that influence drug disposition, and optimize buprenorphine dose and interval of administration. We plan to also build a pharmacometric model of oral morphine in NAS. Our third major aim is to use pharmacogenetics to elucidate sources of variability in the need for pharmacologic treatment in NAS, and the differential response to opioid replacement therapy in this population. To reach achieve these aims, we propose a four year, randomized, blinded, double dummy, single site, parallel group clinical trial in which eighty term infants who require pharmacologic treatment for NAS will be randomized in a 1:1 ratio to each treatment arm. Sparse sampling for PK samples will be analyzed by use of mass spectroscopy. All infants at risk for NAS will have pharmacogenetic samples to allow for comparisons between treated and non-treated infants, as well as a discrimination of response to drug therapy. Patients will be drawn primarily from a well-established comprehensive treatment program for pregnant women treated with methadone for addiction. The research team assembled to perform the trial is extant. Comprehensive expertise to conduct the investigation exists vertically from parent intake, through birth, management of neonatal medical issues, clinical trial administration, analytic chemistry, genetic analysis, biostatistics, and pharmacometric analysis. It is through these investigations that we hope to better understand the biology of addiction, and ultimately improve the treatment options for infants at risk for NAS.